12-alkyl-12-hydroxyprogesterone derivatives



Unite 3,052,694 IZ-ALKYL-IZ-HYDROXYPROGESTERONE DERIVATIVES Percy L.Julian, Oak Park, and Arthur Magnani, Wilmette, 111., assignors to TheJulian Laboratories, Inc.,

Franklin Park, Ill., a corporation of Illinois No Drawing. Filed Oct.14, 1958, Ser. No. 767,099

3 Claims. (Cl. 260397.5)

OH; HO R 6:0

in which R is a lower straight chain alkyl of from 1 to 6 carbons,preferably methyl or ethyl and advantageously methyl.

The compounds of this invention are prepared by reacting a Grignardreagent, such as an alkyl magnesium chloride, bromide or iodide, or ametallic reagent, such as a lithium alkyl, with the keto group of12-ketopregnan- 3a,20,6-diol. The reaction is usually carried out in anonhydroxylated organic solvent in which the reactants have substantialsolubility such as ethyl ether, benzene, tetrahydrofuran, xylene,toluene or mixtures thereof with heating at about 35-100 C., preferablyin boiling benzene, for about one to six hours. When the Grignardreagent is used, the reaction is advantageously carried out directly onthe keto diol intermediate. Alternatively, the 3,20-hydroxyl groups canbe protected prior to the reaction by conventional protective groups,such as tetrahydropyranyl. In this case the tetrahydropyranyl groups areremoved after the addition of the metallic reagent by gentle acidtreatment.

The 12-alkylpregnan-3,12,20-triols are then oxidized, such as by chromicacid in acid solution, such as in acetic acid, or by chromic oxide inbasic solution, such as pyridine, to the diones. These compounds arethen monobrominated at the 4 position and dehydrohalogenated by reactionat about room temperature With semicarbazide in an alkalineaqueous-lower-alcohol mixture followed by pyruvic acid cleavage of thesernicarbazone in acid media to yield the12-alkyl-12-hydroxyprogesterone derivatives of this invention.

The following examples are illustrative of the preparation of thecompounds of this invention and clearly demonstrate the utility of thevarious new intermediates described.

Example 1 A warm solution of 10 g. of 12-ketopregnan-3a,20fi-diol in 250ml. of dry benzene is reacted with stirring with 50 ml. of 3 M etherealmethyl magnesium bromide. After heating at reflux for three hours, themixture is decomposed in an ice hydrochloric acid slurry. The resultingsolid is recrystallized from methanol to give12-methylpregnan-3,12,20-triol, M.P. 218-220" C.

States Patent 0 "ice A sample of the triol is acetylated by Warming inacetic acid and pyridine for an hour to give the diacetate, M.P. 13l-133C.

Example 2 A slurry of 20 g. of 12-ketopregnan-3a,20fl-diol in ml. ofdihydropyran and 0.7 ml. of concentrated hydrochloric acid is stirred atroom temperature for four hours. The next day, ml. of 5% methanolicpotassium hydroxide solution is added. The excess dihydropyran is steamdistilled. The separated oily residue is taken up in benzene. Afterdrying and concentrating, an aliquot of the bis-dihydropyranylderivative (4 g. of diol) is treated with 60 ml. of ethereal lithiumethyl solution prepared from 1 g. of lithium metal and 10 g. of ethyliodide. The solution is stirred for an hour, then heated at reflux fortwo hours. After decomposing in a water-ice-acid slurry, the protectivegroups are removed by warming the syrup in 200 ml. of methanol acidifiedwith 2 ml. of concentrated hydrochloric acid. The pyran is removed bydistillation and the 12-ethylpregnan3,12,20-trio1 separated from theresidue by filtration.

Example 3 A cooled slurry of 18 g. of 12-methylpregnan-3,l2-20 triol in100 ml. of acetic acid is reacted with 10 g. of chromic acid (CrO in 10ml. of water and 25 ml. of acetic acid. After stirring at roomtemperature for one hour, the mixture is quenched in water and the crude12- methylpregnan-12-ol-3,30-dione separated, M.P. 191- 193 0.

Example 4 A solution of 5 g. of bromine in 40 ml. of dimethylformamideis added dropwise over two hours to a solution of 10.4 g. of12-methyl-l2-hydroxypregnan-3,20- dione and 300 mg. of p-toluenesulfonicacid in 100 ml. of dimethylformamide at 30-32 C. The solution is dilutedto 1 l. with water and extracted with ether. The ether, upon drying andevaporating, yields the desired4-bromo-lZ-methylpregnan-12-ol-3,20-dione, M.-P. 148- 150 C.

Example 5 A solution of 6.8 g. of the 4-bromo compound of Example 4 in80 ml. of methylene chloride is treated for one hour at room temperaturewith a solution of 4.5 g. of semicarbazide hydrochloride, 3.4 g. ofsodium bicarbonate, 8 ml. of water and 200 ml. of tertiary butylalcohol. A solution of 10 ml. of pyruvic acid in 18 ml. of water and 80m1. of acetic acid is added. After standing overnight, the product isisolated by extraction into methylene chloride,12-methyl-12-hydroxyprogesterone, MP. 162-- 164 C., [oc]+159 (acetone),E at 241 III/L is 11,500.

Example 6 A mixture of 9.1 g. of 12-ethylpregnan-3,12,20-triol (Example2) and 5 g. of chromic acid in m1. of aqueous acetic acid is allowed toreact at room temperature for two hours. Quenching in water gives12-ethylpregnan-3,20-dione. The dione (5 g.) is monobrominated with 2.5g. of bromine in 75 ml. of dimethylformamide and 100 mg. ofp-toluenesulfonic acid at room temperature. The diluted mixture is takeninto ether to give the 4-bromo derivative. This crude compound (2 g.) isreacted with 1.5 g. of semicarbazide hydrochloride and 1.5 g. ofcarbonate in 100 m1. of aqueous tertiary butanol followed by 3.5 g. ofpyruvic acid as described in Example 5 to give the desired12-ethyl-12-hydroxy progesterone.

Example 7 A solution of 10 g. of 12-ketopregnan-3a,20fl-diol in 250 ml.of dry benzene is reacted with 55 ml. of 3 M ethereal 'hexyl magnesiumbromide. Afer refluxing for three hours, the mixture is quenched in anacidic-ice slurry to give 12-hexy1pregnan-3,12,20-triol. This triol (6g.) is oxidized in 75 ml. of aqueous acetic acid with 3.3 g. of chromicacid for two hours at room temperature. Quenching separates the crudel2-hexylpregnan-12-ol-3,20-dione. The dione (2 g.) is brominated With 1g. of bromine in 50 ml. of dimethylformamide. The 4-brom0 compound (3.7g.) is then dehydrohalogeuated with 2.3 g. of semicarbazide and 5 ml. ofpyruvic acid'as described in Example 5 to give12-hexyl-12-hydroxyprogesterone.

What is claimed is: 1. IZ-methylpregnan-3oz,12,20-triol. 2.12-ethylpregnaJ1-3u,12,20-tri0l. 3. 12-hexylpregnan-3a,12,20-triol.

5. References Cited in the file of this patent UNITED STATES PATENTS2,142,170 Bochmuhl et a1. Ian. 3, 1939 2,857,403 Fried et-al. a Oct. 21,1958 2,934,546 Ringold et a1. Apr. 26, 1960 OTHER REFERENCES Hoehn etal.: J. Am. Chem. Soc., 60, 1493-6 (1938).

Shoppee et al.: Helv. Chim. Acta, 24, 351-60 (1941).

Serkin et al.: Helv. Chim. Acta, 28, 875-91 (1945).

Bush Experientia, vol. 12, Fasc. 9, page 325 (1956).

Fonken: J. Org. Chem., vol. 23, pages 1075-77 (July 1958).

Campbell et al.: I. Am. Chem. Soc., 80, 4717 (1958).

Campbell et al.: I. Am. Chem. Soc., 81, 4069-74 (1959

1. 12-METHYLPREGNAN-3A,12,20-TRIOL.